Disease relevance of GATA3

• Our data suggest that immunohistochemical analysis of GATA3 may be the basis for a new clinically applicable test to predict tumor recurrence early in the progression of breast cancer [1].
• To validate its prognostic utility, we did a tissue microarray analysis on a cohort of 139 consecutive invasive carcinomas (n = 417 tissue samples) immunostained with a monoclonal antibody against GATA3 [1].
• The hazard ratio of metastasis or recurrence according to the GATA3 status was 0.31 (95% confidence interval, 0.13-0.74; P = 0.009) [1].
• Regulation of the human interleukin-5 promoter by Ets transcription factors. Ets1 and Ets2, but not Elf-1, cooperate with GATA3 and HTLV-I Tax1 [2].
• The relative expressions of T-bet/GATA-3 and IFN-g/IL-4 correlated with lupus disease activity (r = 0.229, p = 0.042; r = 0.231, p = 0.040, respectively) [3].

Psychiatry related information on GATA3

• Although GATA-3 expression in hepatocytes increases during human development, erythropoietin mRNA accumulation is unaltered in mutant mice lacking GATA-3 [4].
• Combining cytokine signalling with T-bet and GATA-3 regulation in Th1 and Th2 differentiation: a model for cellular decision-making [5].
• Conditioning therapy included either single-dose total body irradiation (STBI) or fractionated TBI (FTBI) grouped in different dose rates (low: LDR < or = 0.04 Gy/min; high: HDR > 0.04 Gy/min) [6].
• Although reduction in the serum prostate specific antigen (PSA) correlates with clinical outcome for high dose rate Iridium-192 (HDR Ir-192) brachytherapy, it takes a long latency period [7].

High impact information on GATA3

• Before activation, the T(H)2 cytokine locus is already associated with GATA3 and STAT6, showing some looping, but these are insufficient to induce cytokine gene expression [8].
• Further, FOXA1 was identified as a downstream target of GATA-3 in the mammary gland [9].
• This suggests that GATA-3 actively maintains luminal epithelial differentiation in the adult mammary gland, which raises important implications for the pathogenesis of breast cancer [9].
• GATA-3 was found in the luminal cells of mammary ducts and the body cells of terminal end buds (TEBs) [9].
• We identified GATA-3 as the most highly enriched transcription factor in the mammary epithelium of pubertal mice [9].

Chemical compound and disease context of GATA3

• In recent microarray analyses of human breast tumors, both normal breast luminal epithelium and estrogen receptor (ESR1)-positive tumors showed high expression of GATA3 [10].
• 3D interstitial HDR brachytherapy combined with 3D external beam radiotherapy and androgen deprivation for prostate cancer. Preliminary results [11].
• Treatment consisted of 60 minutes of 915 MHz microwave interstitial hyperthermia, followed by iridium-192 seed implants, either by Micro-Selectron HDR (10-12 Gray [Gy] in 8.5-21 minutes) or high activity (5-8 mCi per seed) seeds (10-15 Gy in 2-4 hours) [12].
• Three patients with a choroidal melanoma, treated with HDR (High Dose Rate) Strontium-90 brachytherapy, underwent an enucleation [13].

Biological context of GATA3

• These results show that GATA3 is essential in the embryonic development of the parathyroids, auditory system and kidneys, and indicate that other GATA family members may be involved in the aetiology of human malformations [14].
• Promoter analysis revealed that a GATA site in a cryptic promoter in the second intron was essential and sufficient for the TAL1- and LMO-dependent transcriptional activation, and GATA3 binds to this site [15].
• Thus, our results, which expand the spectrum of HDR-associated GATA3 mutations and report the first acceptor splice site mutation, help to elucidate the molecular mechanisms that alter the function of this zinc finger transcription factor and its role in causing this developmental anomaly [16].
• SNPs of the GATA3 gene showed an initial association to asthma-related phenotypes [17].
• Analysis of GATA3 in the family revealed a heterozygous missense mutation resulting in a nonconservative change of a single amino acid (R276P) in the ZnF1 domain [18].

Anatomical context of GATA3

• GATA binding protein 3 (GATA3) is a transcriptional activator highly expressed by the luminal epithelial cells in the breast [1].
• In contrast, GATA3, T-bet, and NFATc levels were identical in WT and Tg CD4 T cells [19].
• The ectopic expression of GATA3 in human 293T cells caused the induction of 73 genes including six cytokeratins, and inhibited cell line doubling times [10].
• In parallel with the induction of chromatin remodeling, GATA3 mRNA was preferentially expressed in developing Th2 cells, whereas T-bet, HLX and ROG mRNA was selectively expressed in developing Th1 cells [20].
• Overexpression of hGATA-3 in HeLa cells or human B cells specifically activated transcription from a co-transfected reporter plasmid containing two copies of the T alpha 3 binding site located upstream of the minimal SV40 promoter [21].

Associations of GATA3 with chemical compounds

• The functional effects of these mutations, together with a previously reported GATA3 ZnF1 mutation and seven other engineered ZnF1 mutations, were assessed by electrophoretic mobility shift, dissociation, yeast two-hybrid and glutathione S-transferase pull-down assays [16].
• The good prognosis group IE showed high expression of estrogen- and GATA3-regulated genes [22].
• Meanwhile, both positive percentage and relative intensity of gene expression were lower for a type 1 cytokine-related transcription factor T-bet (31.4% and 0.142, respectively) than those for type 2 cytokine-related GATA3 (85.7% and 0.378, respectively) [23].
• These simvastatin-conditioned DCs up-regulated GATA-3 expression and down-regulated T-bet expression in cocultured CD4+ T cells in the absence of additional simvastatin added to the coculture [24].
• Furthermore, 416B cells treated with the DNA demethylating agent 5-azacytidine underwent megakaryocytic differentiation accompanied by a marked increase in the level of GATA-1 mRNA but not that of GATA-2 or GATA-3 [25].

Physical interactions of GATA3

• Megakaryocytic differentiation induced in 416B myeloid cells by GATA-2 and GATA-3 transgenes or 5-azacytidine is tightly coupled to GATA-1 expression [25].
• Using chromatin immunoprecipitation assays, we showed that GATA-3 specifically binds to the NKG2A promoter in situ in NKL and primary NK cells, but not in Jurkat T cells [26].
• This region contains two potential GATA-3-binding sites and increases expression from the hIL-5 promoter by up to ninefold [27].
• Genomic analysis identifies highly conserved GATA-3 binding sites bound in vivo by GATA-3 in the first intron of the lipid acyltransferase gene AGPAT5 [28].
• These results indicate that the GATA-3/T-bet transcription factor complex regulates the cell-lineage-specific expression of the lymphocyte homing receptors [29].

Regulatory relationships of GATA3

• In JEG-3 cells, human GATA-2 (hGATA-2) and hGATA-3 are highly expressed and both proteins bind to the alpha-subunit gene GATA element [30].
• These data suggest that the local recruitment of GR causes repression by inhibiting transcriptional activation by GATA3, a key tissue-specific determinant of expression of Th2 cytokines [31].
• In addition, STAT6 induces expression of the transcription factor GATA3, which also contributes to mu-opioid receptor gene transcription [32].
• In this case, TAL1 and LMO act as cofactors for GATA3 to activate the transcription of RALDH2 [15].
• GATA-3 suppresses IFN-gamma promoter activity independently of binding to cis-regulatory elements [33].
• Reciprocally, ER alpha directly stimulates the transcription of the GATA-3 gene, indicating that these two factors are involved in a positive cross-regulatory loop [34].

Other interactions of GATA3

• This member, called hGATA3, has 85% amino acid homology with hGATA1 in the DNA-binding domain and no homology elsewhere in the protein [35].
• In contrast, GATA-2 is strongly expressed in both most primitive and committed progenitors cells, whereas GATA-3 is mostly detected in most primitive ones [36].
• Repression of interleukin-5 transcription by the glucocorticoid receptor targets GATA3 signaling and involves histone deacetylase recruitment [31].
• These results show, for the first time, that Ets1 and Ets2 are able to cooperate with GATA3 [2].
• To further establish the importance of this region, we obtained 19 kb of sequence and screened for potential binding sites for the MAR-binding protein, SATB1, and for GATA-3, both of which are critical for T cell development [37].

Analytical, diagnostic and therapeutic context of GATA3

• Identification of GATA3 as a breast cancer prognostic marker by global gene expression meta-analysis [1].
• Patients whose tumors expressed low GATA3 had significantly shorter overall and disease-free survival when compared with those whose tumors had high GATA3 levels [1].
• Sequence analysis of GATA3 showed a heterozygous novel mutation in this family: an unusual mutation at exon 3 (709insC) resulting in a premature stop at codon 302 with a loss of both of the zinc finger domains [38].
• Northern blot analyses of hematopoietic cell lines demonstrate that hGATA-3 is expressed exclusively in T cells [21].
• Real time RT-PCR analysis revealed a dampened expression of the Th1-associated gene, T-bet, and a time-dependent increase in the mRNA for the Th2-associated genes, GATA-3, c-MAF and STAT6, upon treatment with ATRA [39].

References